Regulatory Decision Summary for SonoVue

The supporting evidence for this SNDS is derived from published literature. Four studies were identified by the Sponsor as pivotal. The subjects in the pivotal studies were representative of the target population (i.e., pediatric patients). The same dose of SonoVue (1.0 mL) was used in all four studies and is representative of the proposed dose. The efficacy endpoints (i.e., sensitivity and specificity) were the same in all four studies. All studies used the same reference standard, which was voiding cystourethrography (VCUG). A meta-analysis of the four pivotal studies was also performed.

Overall, 508 paediatric patients, with a total of 1,023 ureter units, were included in the four studies. Patients in the studies ranged in age from 2 days to 13 years, and slightly more than half of the patients were male (N = 275, 54.1%).

The sensitivity of SonoVue-enhanced ultrasonography (US) for detection of VUR across four pivotal studies ranged between 80% and 100%, with specificity ranging between 77% and 86%. Based on the combined data, VUS with SonoVue displayed a pooled sensitivity of 89% (95% CI: 80% to 97%), and a pooled specificity of 81% (95% CI: 76% to 86%).

The submitted evidence supports the expansion of the indication to the target population (i.e., pediatric patients) for the evaluation of suspected or known vesicoureteral reflux.

The safety data of SonoVue for the intravesical administration are mainly based on published data, as post-marketing surveillance information for SonoVue are limited.

Non-serious minor adverse events were reported in 37 patients out of 1,010 children. Dysuria (i.e., painful or difficult urination) was the most frequently reported event and occurred in 26 children. All reported events were self-limiting and none required hospitalization. None of the reported events were considered related to SonoVue, but they were related to the catheterisation procedure during VUS.

As disruption of the bladder permeability barrier in certain pathologic conditions including bacterial infection cannot be excluded in patients with Urinary Tract Infection (UTI), the precautionary statement that the safety of SonoVue administration to children in the active phase of UTI has not been established was added to the Product Monograph.

Overall, the submitted evidence supports the expansion of the indication to the target population (i.e., pediatric patients) for the evaluation of suspected or known vesicoureteral reflux. The safety profile of SonoVue for the proposed indication is favorable. The safety limitations are managed via labelling.